Process for preparation of glycidyl ether

ABSTRACT

A process for preparation of a glycidyl ether which is characrelized in reacting an epoxy compound of the formula ##STR1## wherein X is halogen or sulfonyloxy in the presence of a fluoride salt, with an alcohol. According to the above method, glycigyl ethers or their optically active compounds important as intermediates for synthesis of medicines are easily obtained in good yield and especially the optically active compounds are obtained with highly optical purity.

This application is a 371 of PCT/JP97/03221, dated Sep. 12, 1997.

1. TECHNICAL FIELD

The present invention relates to a process for preparation of glycidylethers and optical active compounds thereof important as intermediatesfor synthesis of medicines and physiologically active compounds.

2. BACKGROUND ART

Glycidyl ethers are important intermediates for synthesis of many kindsof medicines. For example, so called β-receptor blocking agents whichare often used as circulatory drugs, especially antihypertensive agentsand antiarrhythmic agents, are basically prepared from glycidyl ethers.

The glycidyl ethers have been prepared by reacting a correspondingalcohol with an epoxy compound, such as epichlorohydrin or glycidylp-toluenesulfonate. The reaction of the alcohol with epichlorohydrin orglycidyl p-toluenesulfonate is carried out in the presence of an alkalimetal base, such as sodium hydride or sodium hydroxide, or an organicbase, such as triethylamine or pyridine, or in the presence of catalyst,such as a mineral acid (e.g., sulfuric acid) or Lewis acid (e.g., tintetrachloride) to prepare a 3-chloro or tosyloxy-2-propanol derivativeand it was treated with a base to prepare a glycidyl ether. However, incase of carrying out in the base i n the former, the epoxy compound,such as epichlorohydrin or glycidyl p-toluenesulfonate must be used inexcess and therefore, the reaction is not economical. In case of using astrong base, such as sodium hydride or sodium hydoxide, theafter-treatment, such as neutralization is necessary and it istroublesome. In case of using sodium hydride there is a possibility ofburning in the after-treatment. On the other hand, in case of the latterin acidic conditions the reaction steps are many and the treatment istroublesome. Furthermore, in case of using an aryl derivative having asubstituent unstable in basic conditions, the yield is not good.

By the way, glycidyl ethers have an asymmetric carbon atom and exist inoptical isomers. Recently in developing the medicines comprising opticalisomers, each isomer is investigated. Therefore, it becomes veryimportant to establish a method to prepare easily an optically activecompound with highly optical purity of these compounds. In order tosolve such problems, combinations of many kinds of bases with anoptically active epichlorohydrin, glycidyl p-toluenesulfonate, orglycidyl m-nitrobenzenesulfonate have been investigated. These methods,for instance, are described in Japanese Patent Publication No. 1-121282,Japanese Patent Publication No. 1-279890, Japanese Patent PublicationNo. 1-279887, European Patent No. 454385, Japanese Patent Publication BNo. 6-37449, Chem. Pharm. Bull., 35, 3691 (1987), Chem. Pharm. Bull.,38, 2092 (1990), J. Org. Chem., 54, 1295 (1989) and so on.

However, in all these methods, marked racemization occurs on thereaction and the optical purity decreases.

Optical purity of an glycidyl ether prepared by reactingp-hydroxyphenylacetoamide and an optically active epichlorohydrin insodium hydroxide as a base decreases to 90% e.e. and it is notsatisfactory.

The present inventors engaged extensively in solving above problems, andfound to prepare easily and with good yield a glycidyl ether by reactingan epoxy compound and an alcohol in the presence of a fluoride salt.Furthermore, when an optically active epoxy compound is used, the objectcompound obtained is also optically active, and marked racemization doesnot occur on the reaction.

DISCLOSURE OF INVENTION

The present invention relates to a process for preparation of a glycidylether of the formula ##STR2## wherein R is substituted or unsubstitutedalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heterocyclic ring,

which is characterized in reacting an epoxy compound of the formula##STR3## wherein X is halogen or sulfonyloxy group, with an alcohol ofthe formula

    ROH                                                        (2)

wherein R is as defined above,

in the presence of a fluoride salt.

Examples of halogen shown by X in the formula (1) are chlorine atom,bromine atom and iodine atom, preferably chlorine atom and bromine atom.Examples of sulfonyloxy group shown by X in the formula (1) arepreferably a substituted or unsubstituted alkylsulfonyloxy having 1 to10 carbon atoms, such as methanesulfonyloxy ortrifluoromethanesulfonyloxy, a substituted or unsubstitutedarylsulfonyloxy, such as benzenesulfonyloxy, p-toluenesulfonyloxy orm-nitrobenzenesulfonyloxy.

Examples of the epoxy compound of the formula (1) are epichlorohydrin,epibromohydrin, glycidyl methanesulfonate, glycidyltrifluoromethanesulfonate, glycidyl ethanesulfonate, glycidylpropanesulfonate, glycidyl butanesulfonate, glycidylphenylmethanesulfonate, glycidyl p-trifluoromethylbenzenesulfonate,glycidyl benzenesulfonate, glycidyl p-toluenesulfonate, glycidyl2,4,6-triisopropylbenzenesulfonate, glycidylp-tert-butylbenzenesulfonate, glycidyl p-chlorobenzenesulfonate,glycidyl p-bromobenzenesulfonate, glycidyl p-iodobenzenesulfonate,glycidyl 2,4,5-trichlorobenzenesulfonate, glycidylo-nitrobenzenesulfonate, glycidyl m-nitrobenzenesulfonate, glycidylp-nitrobenzenesulfonate, glycidyl 2,4-dinitrobenzenesulfonate, glycidylp-methoxybenzenesulfonate, glycidyl 4-chloro-3-nitrobenzenesulfonate,glycidyl 1-naphthalenesulfonate, glycidyl 2-naphthalenesulfonate and soon. Glycidyl m-nitrobenzenesulfonate, glycidyl p-toluenesulfonate andepichlorohydrin are preferably used among them.

Examples of the alcohol of the formula (2) are alkanols having 1 to 10carbon atoms, such as methanol, ethanol, propanol, butanol, isopropylalcohol, isobutyl alcohol, t-butyl alcohol, sec-butyl alcohol and thelike, alkanols substituted by a phenyl, such as benzyl alcohol,α-phenethyl alcohol, β-phenethyl alcohol and the like, alkanolssubstituted by a phenyl having substitutent(s), such as p-methoxybenzylalcohol, p-nitrobenzyl alcohol and the like. Aromatic alcohols are alsoused, such as phenol and aromatic alcohols having substituent(s). Thesubstituents are not limited as far as they do not prevent thisreaction, and include saturated or unsatulated alkyls, such as methy,ethyl, allyl and the like, alkyls having ether bond(s), such asmethoxymethyl, 2-methoxyethyl, allyloxymethyl, (2-methoxyethoxy)methyl,(2-isopropoxyethoxy)methyl and the like, nitro, halogen, such asfluorine atom, chlorine atom, bromine atom and iodine atom,trifluoromethyl, alkoxys, such as methoxy, allyloxy, methoxymethoxy andthe like, cyano, cyanomethyl, alkoxycarbonyls, such as methoxycarbonyl,ethoxycarbonyl and the like, acyloxys, such as acetoxy and the like,amides, such as acetylamide and the like, carbamoyl, carbamoylmethyl,aldehyde, acyls, such as acetyl, benzoyl and the like. Furthermore, thesubstituent includes one and more substituents and may form a bridge,such as tetramethylene or methylenedioxy with the other substituent. Thesubstituents, alkyls may be further substituted by another substituent.

The above aromatic alcohol includes a polycyclic aromatic compoundhaving hydroxy. A heterocyclic compound having hydroxy can be also used.Examples of them are polycyclic aromatic alcohols, such as α-naphthol,β- naphthol, 7-hydroxyindene and the like, heterocyclic compoundssubstituted by hydroxy, such as 3-hydroxypyridine,3-hydroxytetrahydrofuran, 4-hydroxyindole, 5-hydroxyquinoline and so on.

Preferable alcohols of the formula (2) are aromatic alcohols andheterocyclic compounds having hydroxy, especially o-allylphenol,o-allyloxyphenol, 4-hydroxyindole, p-(2-isopropoxyethoxy)methylphenol,α-naphthol and carbamoylmethylphenol.

The amount of the alcohol of the formula (2) is 0.5 to 3 mole equivalentto epoxy compound (1), preferably 0.8 to 1.2 mole equivalent. To use itmore than 3 mole equivalent does not affect, but is not economical. Onthe other hand, to use it less than 0.5 mole equivalent causes to leavemuch amount of an unreacted epoxy compound and it is not economical.

Preferable examples of the fluoride salts used in this reaction arequaternary ammonium fluorides, alkali metal fluorides and alkaline earthmetal fluorides, especially alkali metal fluorides and alkaline earthmetal fluorides. These may be used alone or in combination of them andmay be in form being supported on a carrier.

Examples of the quaternary ammonium fluorides are tetramethylammoniumfluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride,tetraoctylammonium fluoride, benzyltrimethylammonium fluoride, etc.Examples of the alkali metal fluorides are sodium fluoride, potassiumfluoride and cesium fluoride. Examples of the alkaline earth metalfluorides are magnesium fluoride and calcium fluoride. Examples of thecarriers are Celite, alumina, silica gel, molecular sieves, its modifiedmaterial and so on.

The amount of the fluoride salt is 0.5 to 6 mole equivalent to epoxycompound of the formula (1), preferably, 0.9 to 6 mole equivalent. Touse it less than 0.5 mole equivalent does not make the reaction completeand to use more than 6 mole equivalent cause difficult to stir thereaction mixture. In case of using a fluoride salt together with analkali metal hydrogen carbonate or carbonate mentioned below, the amountof the fluoride salt can reduced to 0.05 mole equivalent to the epoxycompound. Even in case of using it less than 0.05 mole equivalent thereaction proceeds, but it takes much hours in the reaction and is notpractical.

Examples of solvents used in this reaction are polar aprotic solvents,such as N,N-dimethylformamide, dimethyl sulfoxide, sulforane,hexamethylphosphoramide and the like, esters, such as ethyl acetate,butyl acetate and the like, ethers, such as tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, t-butylmethyl ether, diethyl ether andthe like, ketones, such as acetone, methyl ethyl ketone, methyl isobutylketone and the like, nitrites, such as acetonitrile and the like, and amixture of these solvents. Preferable ones are tetrahydrofuran,t-butylmethyl ether and actonitrile, more preferablyN,N-dimethylformamide.

The reaction proceeds without catalyst, but the reaction is acceleratedby adding N,N-dimethylaminopyridine, alkali metal or alkaline earthmetal halides, such as cesium iodide, potassium bromide, sodium bromide,magnesium bromide, calcium bromide, potassium iodide, sodium iodide,magnesium iodide and calcium iodide, quaternary ammonium salts, such astetrabutylammonium fluoride, terabutylammonium chloride,benzyltrimethylammonium bromide and the like, crown ethers, such as18-Crown-6 and the like. The amount of the catalyst is 0.1-50 molepercentage per alcohol(2).

The mechanism of the reaction is not clear, but the reaction proceed inneutral conditions and it seems that the resulting acid is caught by afluoride salt. In fact, when a week base, such as an alkali metal oralkaline earth metal hydrogen carbonate or carbonate as an acid trappingagent is added, the reaction is accelerated and the amount of thefluoride salt can be reduced. Therefore, it is effective to add analkali metal or alkaline earth metal hydrogen carbonate or carbonate,such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodiumcarbonate, potassium carbonate, calcium carbonate, magnesium carbonate,barium carbonate and the like, thereto. Its amount is not limited, butusually 0.1 to 10 mole equivalent to alcohol of the formula (2),preferably 1 to 3 mole equivalent is used.

The reaction temperature is -50° C. to boiling point of the solventused, preferably -10 to 100° C. In case of the temperature being toolow, the reaction rate becomes low, and in case of the temperature beingtoo high, degradation of the starting materials or product occurs andthe yield of the product decreases. Furthermore, when an opticallyactive epoxy compound is used, racemization occurs at the reactiontemperature of more than 100° C. and therefore, such the hightemperature is not preferable.

Regarding post treatment after the reaction, insoluble materials arefiltered off, water is added thereto and the object compound isextracted with an organic solvent, or after the removal of insolublematerials, the filtrate may be subjected to, after removal of thesolvent, distillation, recrystallization, or column chromatography toprepare the object compound. Therefore, these procedures are very simpleand do not need any such complex procedure as the old procedure needs toreact carefully the excess strong base with water or dilutedhydrochloric acid and make neutralization treatment and extraction.

According to the present invention, in case of using an optically activeepoxy compound as a starting material, an optically active glycidylether is obtained. In case of using an epoxy compound with highlyoptical purity, marked racemization does not occur on the reaction thereis obtained a glycidyl ether with highly optical purity.

The present invention is explained in detail by following examples.

REFERENCE EXAMPLE 1 Preparation of Potassium Fluoride/Alumina

Potassium fluoride (58.1 g) was dissolved in water (about 300 ml) andpowdered alumina (neutral, 100 g) were added thereto. Water wasdistilled off in vacuo and the residue was dried in vacuo.

REFERENCE EXAMPLE 2 Preparation of Sodium Fluoride/Calcium Fluoride

Sodium fluoride (42.0 g) was dissolved in water (about 300 ml) andcalcium fluoride (78.1 g) was added thereto and mixture was stirredwell. After removal of water in vacuo the residue was dried in vacuo.

EXAMPLE 1

p-Hydroxyphenyl acetamide (1 g) was dissolved in N,N-dimethylfomamide(DMF, 5 ml) under nitrogen atmosphere and the solution was cooled to 0°C. Cesium fluoride (3.02 g) was added thereto, and the mixture wasstirred for 1 hour. Then, S-glycidyl m-nitrobenzenesulfonate (1.71 g,99.3% e.e.) was added thereto and the mixture was stirred for 12 hoursat the same temperature. After the reaction, water was added to themixture, the mixture was extracted with ethyl acetate, dried overanhydrous magnesium sulfate, condensed and the residue was subjected tosilica gel chromatography (hexane/ethyl acetate; 1:1) to give 1.31 g of(S)-1-[p-(carbamoylmethyl)phenoxy]-2,3-epoxypropane (yield 96%, opticalpurity 99.3% e.e.) as colorless crystals.

m.p. 167.8-169.1° C.

[α]_(D) (21° C., c=0.5, CH₃ OH)=+10.9°

NMR(DMSO-d6) δ:2.65-2.73(1H, m), 2.83(1H, dt), 3.29(1H, s), 3.33(1H, m),3.80(1H, ddd), 4.29(1H, ddd), 6.82(1H, brs), 6.89(2H, d), 7.17(2H, d),7.39(1H, brs)

EXAMPLE 2

Phenol (1.09 g) was dissolved in DMF (5 ml) under nitrogen atmosphereand the solution was cooled to 0° C. Cesium fluoride (2.29 g) was addedthereto, and the mixture was stirred for 1 hour. Then, R-glycidylm-nitrobenzenesulfonate (3.0 g, 99.3% e.e.) was added thereto and themixture was stirred for 12 hours at the same temperature. After thereaction, water was added to the mixture, the mixture was extracted withethyl acetate, dried over anhydrous magnesium sulfate, condensed and theresidue was subjected to silica gel chromatography (hexane/ethylacetate; 50:1) to give 1.55 g of (R)-2,3-epoxyphenol (yield 89%, opticalpurity 98.5% e.e.) as a colorless oil.

[α]_(D) (21° C., c=2.86, CH₃ OH)=-15.1°

NMR(CDCl3) δ:2.76(1H, m), 2.90(1H, m), 3.30-3.45(1H, m), 3.96(1H, dd),4.21(1H, m), 6.85-7.09(3H, m), 7.21-7.41(2H, m)

EXAMPLE 3

o-Allyloxyphenol (1.0 g) was dissolved in DMF (5 ml) under nitrogenatmosphere and the solution was cooled to 0° C. Cesium fluoride (1.52 g)was added thereto and the mixture was stirred for 1 hour. Then,R-glycidyl m-nitrobenzenesulfonate (1.73 g, 99.3% e.e.) was addedthereto and the mixture was stirred for 12 hours at the sametemperature. After the reaction, water was added to the mixture, themixture was extracted with ethyl acetate, dried over anhydrous magnesiumsulfate, condensed and the residue was subjected to silica gelchromatography (hexane/ethyl acetate; 3:2) to give 1.32g of(R)-3-[o-allyoxyphenoxy]-1,2-epoxypropane (yield 96%, optical purity99.3% e.e.) as a colorless oil.

[α]_(D) (21° C., c=1.0, CH₃ OH)=-15.0°

NMR(CDCl3) δ:2.75, 2.87(2H, 2q), 3.34(1H, m), 4.03, 4.25(2H, 2q),4.59(2H, m), 5.27, 5.41(2H, 2q), 6.08(1H, 2q), 6.87-6.98(4H, m)

EXAMPLE 4

1-Naphthol (1.0 g) was dissolved in DMF (8 ml) under nitrogen atmosphereand the solution was cooled to 0° C. Cesium fluoride (2.11 g) was addedthereto and the mixture was stirred for 1 hour. Then, (S)-glycidylm-nitrobenzenesulfonate (1.80 g, 99.3% e.e.) was added thereto and themixture was stirred for 24 hours at the same temperature. After thereaction, water was added to the mixture, the mixture was extracted withethyl acetate, dried over anhydrous magnesium sulfate, condensed and theresidue was subjected to silica gel chromatography (hexane/ethylacetate; 6:1) to give 1.34 g of (S)-1-(2,3-epoxypropoxy)naphthalene(yield 96.5%, optical purity 99.2% e.e.) as a colorless oil.

[α]_(D) (21° C., c=1.0, CHCl₃)=+16.9°

NMR(CDCl3) δ:2.85(1H, m), 2.96(1H, m), 3.43-3.51(1H, m), 4.11(1H, dd),4.40(1H, m), 6.80(1H, d), 7.32-7.52(4H, m), 7.74-7.83(1H, m),8.24-8.34(2H, m)

EXAMPLE 5

4-Hydroxyindole (3.0 g) was dissolved in DMF (10 ml) under nitrogenatmosphere and the solution was cooled to 0° C. Cesium fluoride (10.12g) was added thereto and the mixture was stirred for 1 hour. Then(S)-glycidyl m-nitrobenzenesulfonate (5.84 g, 99.3% e.e.) was addedthereto and the mixture was stirred for 30 hours at the sametemperature. After the reaction, water was added to the mixture, themixture was extracted with ethyl acetate, dried over anhydrous magnesiumsulfate, condensed and the residue was subjected to silica gelchromatography (hexane/isopropyl alcohol; 20:1) to give 4.01 g of(S)-4-(2,3-epoxypropoxy)indole (yield 94.1%, optical purity 99.2% e.e.)as a colorless oil.

[α]_(D) (24° C., c=0.5, CH₃ OH)=+28.2°

NMR(CDCl3) δ:2.66(1H, dd), 2.77(1H, t), 3.27-3.33(1H, m), 3.94(1H, dd),4.22(1H, dd), 6.38(1H, d), 6.55-6.57(1H, m), 6.84-7.00(3H, m), 8.20(1H,brs)

EXAMPLE 6

4-Hydroxyphenylacetamide (1 g) was dissolved in DMF (10 ml) undernitrogen atmosphere and the solution was cooled to 0° C. Cesium fluoride(2.01 g) was added thereto and the mixture was stirred for 1 hour. Then,(S)-glycidyl p-toluenesulfonate (1.50 g, 98.9% e.e.) was added theretoand the mixture was stirred for 30 hours at the same temperature. Afterthe reaction, water was added to the mixture, the mixture was extractedwith ethyl acetate, dried over anhydrous magnesium sulfate, condensedand the residue was subjected to silica gel chromatography (hexane/ethylacetate; 1:1) to give 1.16 g of(S)-1-[p-carbamoylmethyl)phenoxy]-2,3-epoxypropane (yield 84.7%, opticalpurity 98.0% e.e.) as colorless crystals.

EXAMPLE 7

p-Hydroxyphenylacetamide (1 g) was dissolved in DMF (5 ml) undernitrogen atmosphere and the solution was cooled to 0° C. Cesium fluoride(3.02 g) and sodium iodide (0.1 g) were added thereto and the mixturewas stirred for 1 hour. Then (R)-epichlorohydrin (0.62 g, 98.4% e.e.)was added thereto and the mixture was stirred for 30 hours at the sametemperature. After the reaction, water was added to the mixture, themixture was extracted with ethyl acetate, dried over anhydrous magnesiumsulfate, condensed and the residue was subjected to silica gelchromatography (hexane/ethyl acetate; 1:1) to give 1.22 g of(S)-1-[p-carbamoylmethyl)phenoxy]-2,3-epoxypropane (yield 89%, opticalpurity 98.0% e.e.) as colorless crystals.

EXAMPLE 8

4-Hydroxyphenylacetamide (1 g) was dissolved in DMF (10 ml) undernitrogen atmosphere and the solution was cooled to 0° C. Cesium fluoride(0.20 g) and potassium carbonate (1.19 g) were added thereto and themixture was stirred for 1 hour. Then (S)-glycidylm-nitrobenzenesulfonate (1.71 g, 99.3% e.e.) was added thereto and themixture was stirred for 12 hours at the same temperature. After thereaction inorganic materials were filtered off, and water was added tothe filtrate. The mixture was extracted with ethyl acetate, dried overanhydrous magnesium sulfate, condensed and the residue was subjected tosilica gel chromatography (hexane/ethyl acetate; 1:1) to give 1.29 g of(S)-1-[p-carbamoylmethyl)phenoxy]-2,3-epoxypropane (yield 94.2%, opticalpurity 99.2% e.e.) as colorless crystals.

EXAMPLE 9

o-Allyloxyphenol (1.0 g) was dissolved in tetrahydrofuran (THF, 10 ml)under nitrogen atmosphere and the solution was cooled to 0° C. Potassiumfluoride (1.55 g) and 18-Crown-6 (0.17 g) were added thereto and themixture was stirred for 1 hour. Then (R) -glycidylm-nitrobenzenesulfonate (1.73 g, 99.3% e.e.) was added thereto and themixture was stirred for 40 hours at the same temperature. After thereaction, water was added to the mixture, the mixture was extracted withethyl acetate, dried over anhydrous magnesium sulfate, condensed and theresidue was subjected to silica gel chromatography (hexane/ethylacetate; 3:2) to give 1.07 g of(R)-3-(o-allyloxyphenoxy)-1,2-epoxypropane (yield 78%, optical purity96.26% e.e.) as a colorless oil.

EXAMPLE 10

o-Allyloxyphenol (1.0 g) was dissolved in THF (10 ml) under nitrogenatmosphere and the solution was cooled to 0° C. Potassium fluoride (1.55g) and tetrabutyl ammonium fluoride (0.2 g) were added thereto and themixture was stirred for 1 hour. Then, (R)-glycidylm-nitrobenzenesulfonate (1.73 g, 99.3% e.e.) was added thereto and themixture was stirred for 40 hours at the same temperature. After thereaction, water was added to the mixture, the mixture was extracted withethyl acetate, dried over anhydrous magnesium sulfate, condensed and theresidue was subjected to silica gel chromatography (hexane/ethylacetate; 3:2) to give 0.96 g of(R)-3-(o-allyloxyphenoxy)-1,2-epoxypropane (yield 70%, optical purity95.9% e.e.) as a colorless oil.

EXAMPLE 11

o-Allyloxyphenol (1.0 g) was dissolved in acetonitrile (15 ml) undernitrogen atmosphere and the solution was cooled to 0° C. Potassiumfluoride/alumina (2 g) prepared in Reference Example 1 was added theretoand the mixture was stirred for 1 hour. Then, (R)-glycidylm-nitrobenzenesulfonate (1.73 g, 99.3% e.e.) was added thereto and themixture was stirred for 30 hours at the same temperature. After thereaction, a solid material was filtered off and water was added to thefiltrate. The solution was extracted with ethyl acetate, dried overanhydrous magnesium sulfate, condensed and the residue was subjected tosilica gel chromatography (hexane/ethyl acetate; 3:2) to give 1.22 g of(R)-3-(o-allyoxyphenoxy)-1,2-epoxypropane (yield 89%, optical purity98.0% e.e.) as a colorless oil.

EXAMPLE 12

o-Allyloxyphenol (1.0 g) was dissolved in DMF (15 ml) under nitrogenatmosphere and the solution was cooled to 0° C. Potassiumfluoride/calcium fluoride (4 g) prepared in Reference Example 2 wereadded thereto, and the mixture was stirred for 1 hour. Then,(R)-glycidyl m-nitrobenzenesulfonate (1.73 g, 99.3% e.e.) was addedthereto and the mixture was stirred for 38 hours at the sametemperature. After the reaction, a solid material was filtered off andwater was added to the filtrate. The solution was extracted with ethylacetate, dried over anhydrous magnesium sulfate, condensed and theresidue was subjected to silica gel chromatography (hexane/ethylacetate; 3:2) to give 0.82 g of(R)-3-(o-allyoxyphenoxy)-1,2-epoxypropane (yield 60%, optical purity98.0% e.e.) as a colorless oil.

EXAMPLE 13

p-(2-Isopropoxyethoxy)methylphenol (5 g) was dissolved in DMF (30 ml)under nitrogen atmosphere and the solution was cooled to 0° C. Cesiumfluoride (0.72 g) and potassium carbonate (4.27 g) were added thereto,and the mixture was stirred for 1 hour. Then (S)-glycidylm-nitrobenzenesulfonate (6.16 g, 99.7% e.e.) was added thereto and themixture was stirred for 24 hours at the same temperature. After thereaction, water was added to the filtrate, the solution was extractedwith ethyl acetate, dried over anhydrous magnesium sulfate, condensedand the residue was subjected to silica gel chromatography (hexane/ethylacetate; 1:1) to give 6.08 g of(S)-1-(p-2-isopropoxyethoxymethylphenoxy)-2,3-epoxypropane (yield 96%,optical purity 99.6% e.e.) as a colorless oil.

[α]_(D) (21° C., c=1.0, CH₃ OH)=+9.5°

NMR(CDCl3) δ:1.17(6H, d), 2.75(1H, dd), 2.90(1H, t), 3.32-3.37(1H, m),3.58-3.68(5H, m), 3.95(1H, dd), 4.21(1H, dd), 4.51(2H, s), 6.88-7.29(4H,m)

EXAMPLE 14

4-(2-Isopropoxyethoxy)methylphenol (2.10 g) was dissolved in DMF (7.5ml) under nitrogen atmosphere. Tetrabutylammonium fluoride (7.84 g) wasadded thereto and the mixture was stirred for 1 hour. Then, (S)-glycidylm-nitrobenzenesulfonate (2.59 g, 99.3% e.e.) was added thereto and themixture was stirred for 40 hours at room temperature. After thereaction, water was added to the mixture, the mixture was extracted withethyl acetate, dried over anhydrous magnesium sulfate, condensed and theresidue was subjected to silica gel chromatography (hexane/ethylacetate; 3:2) to give 1.76 g of(S)-3-[4-(2-isopropoxyethoxy)methyl]phenoxy-1,2-epoxypropane (yield 66%,optical purity 97.3% e.e.) as a colorless oil.

EXAMPLE 15

4-(2-Isopropoxyethoxy)methylphenol (2.10 g) was dissolved in DMF (7.5ml) under nitrogen atmosphere. Potassium carbonate (1.80 g) andtetrabutylammonium fluoride (523 mg) were added thereto and the mixturewas stirred for 1 hour. Then (S)-glycidyl m-nitrobenzenesulfonate (2.59g, 99.3% e.e.) was added thereto and the mixture was stirred for 48hours at room temperature. After the reaction, water was added to themixture, the mixture was extracted with ethyl acetate, dried overanhydrous magnesium sulfate, condensed and the residue was subjected tosilica gel chromatography (hexane/ethyl acetate; 3:2) to give 2.48 g of(S)-3-[4-(2-isopropoxyethoxy)methyl]phenoxy-1,2-epoxypropane (yield 93%,optical purity 97.7% e.e.) as a colorless oil.

COMPARATIVE EXAMPLE 1

p-Hydroxyphenyl acetamide (30.02 g) was dissolved in 106.5 g of watercontaining sodium hydroxide (9.6 g) and the solution was cooled to 5° C.Epichlorohydrin (18.5 g, 98.9% e.e.) was dropped in the solution over aperiod of 10 minutes under stirring at the same temperature and thesolution was stirred for 24 hours. Sodium hydroxide (2.4 g) was addedthereto and the mixture was stirred for 5 hours. Resulting crystals werefiltrated by suction, washed with water and dried in vacuo to give crude(S)-1-[p-(carbamoylmethyl)phenoxy]-2,3-epoxypropane (39.8 g). Theoptical purity of it was 91.2% e.e. by measurement of Chiral column OD(Daisel Chemical Industries Ltd.).

COMPARATIVE EXAMPLE 2

o-Allyloxyphenol (1 g) was dissolved in DMF (5 ml) under nitrogenatmosphere and the solution was cooled to 0° C. Sodium hydride (0.32 g,60% in oil), after the oil therein was washed with hexane, was added thesolution under stirring for 30 minutes. Then, 1.52 g of (R)-glycidylp-toluenesulfonate (98.5% e.e.) dissolved in DMF (5 ml) was dropped inover a period of 30 minutes and stirred for 9 hours. After the reaction,thereto ice water was added, neutralized with 0.1% hydrochloric acid,and extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate and condensed to give 1.35g of crude (R)-3-(o-allyloxyphenoxy-1,2-epoxypropane. The optical purityof it was 92.6% e.e. by measurement of Chiral column OD (Daisel ChemicalIndustries Ltd.).

COMPARATIVE EXAMPLE 3

p-Hydroxyphenylacetamide (1 g) and (S)-glycidyl p-toluenesulfonate (1.51g, 99.3% e.e.) were dissolved in acetone (30 ml). Potassium carbonate(1.19 g) was added to the solution and the solution was stirred for 30hours under refluxing. After the reaction, inorganic materials werefiltered off and acetone was removed to give 1.43 g of crude(S)-1-[p-(carbamoylmethyl)phenoxy-2,3-epoxypropane. The optical purityof it was 62.8% e.e. by measurement of Chiral column OD (Daisel Chemicalindustries Ltd.).

According to the present invention, glycidyl ethers important asintermediates for synthesis of medicines and physiologically activecompounds are prepared very easily and with good yield. Especially incase of using an optically active epoxy compound, there is obtained theobject compound with highly optical purity without any markedracemization.

We claim:
 1. A process for preparation of a glycidyl ether of theformula ##STR4## wherein R is substituted or unsubstituted alkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheterocyclic ring,which is characterized in reacting an epoxy compoundof the formula ##STR5## wherein X is halogen or sulfonyloxy group, withan alcohol of the formula

    ROH                                                        (2)

wherein R is as defined above,in the presence of a fluoride salt.
 2. Theprocess for preparation of a glycidyl ether of claim 1 which ischaracterized in reacting in the presence of a fluoride salt, and analkali metal or alkaline earth metal hydrogen carbonate or carbonate. 3.The process for preparation of a glycidyl ether claim 1 which ischaracterized in reacting in the presence of a compound selected from analkali metal or alkaline earth metal halides, quaternary ammoniumhalides and crown ethers.
 4. The process for preparation of a glycidylether of claim 1 wherein the epoxy compound (1) is glycidylm-nitrobenzenesulfonate, glycidyl p-toluenesulfonate or epichlorohydrin.5. The process for preparation of a glycidyl ether of claim 1 whereinthe alcohol (2) is one having a substituted or unsbstituted aromaticring, or a substituted or unsubstituted heterocyclic ring.
 6. Theprocess for preparation of a glycidyl ether of claim 1 wherein thealcohol (2) is phenol or a phenol derivative.
 7. The process forpreparation of glycidyl ether of claim 1 wherein the alcohol (2) iso-allylphenol, o-allyloxyphenol, 4-hydroxyindole,p-(2-isoprpoxyethoxy)mehylphenol, α-naphthol or p-carbamoylmethylphenol.8. The process for preparation glycidyl ether of claim 1 wherein thefluoride salt is an alkali metal or alkaline earth metal fluoride. 9.The process for preparation of a glycidyl ether of claim 1 which ischaracterized in preparing an optically active glycidyl ether from anoptically active epoxy compound.